Method and apparatus for rapid and selective tissue ablation with cooling

ABSTRACT

Systems, tools and methods are disclosed for the selective and rapid application of DC voltage to drive irreversible electroporation, with the system controller capable of being configured to apply voltages to independently selected subsets of electrodes and capable of generating at least one control signal to maintain the temperature near an electrode head within a desired range of values. Electrode clamp devices are also disclosed for generating electric fields to drive irreversible electroporation while modulating temperature to elevate the irreversible electroporation threshold utilizing a variety of means such as cooling fluid or solid state thermoelectric heat pumps.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.15/354,475 titled “METHOD AND APPARATUS FOR RAPID AND SELECTIVE TISSUEABLATION WITH COOLING,” filed Nov. 17, 2016, now issued U.S. Pat. No.10,624,693, which is a continuation of PCT Application No.PCT/US2015/035582 titled “METHOD AND APPARATUS FOR RAPID AND SELECTIVETISSUE ABLATION WITH COOLING,” filed Jun. 12, 2015, which claims thebenefit of priority to U.S. Provisional Application Serial No.61/997,869, titled “Methods and Apparatus for Rapid and Selective TissueAblation with Cooling,” filed Jun. 12, 2014, the entire disclosures ofeach of which are incorporated herein by reference in their entirety.

BACKGROUND

The embodiments described herein relate generally to medical devices fortherapeutic electrical energy delivery, and more particularly to systemsand methods for delivering electrical energy in the context of ablatingtissue rapidly and selectively by the application of suitably timedpulsed voltages that generate irreversible electroporation of cellmembranes, in conjunction with the application of suitable regionalcooling to enhance electroporation selectivity and efficacy.

In the past decade or two the technique of electroporation has advancedfrom the laboratory to clinical applications, while the effects of briefpulses of high voltages and large electric fields on tissue has beeninvestigated for the past forty years or more. It has been known thatthe application of brief high DC voltages to tissue, thereby generatinglocally high electric fields typically in the range of hundreds ofVolts/centimeter can disrupt cell membranes by generating pores in thecell membrane. While the precise mechanism of this electrically-drivenpore generation or electroporation is not well understood, it is thoughtthat the application of relatively large electric fields generatesinstabilities in the lipid bilayers in cell membranes, causing theoccurrence of a distribution of local gaps or pores in the membrane. Ifthe applied electric field at the membrane is larger than a thresholdvalue, the electroporation is irreversible and the pores remain open,permitting exchange of material across the membrane and leading toapoptosis or cell death. Subsequently the tissue heals in a naturalprocess.

Some known processes of adipose tissue reduction by freezing, also knownas cryogenically induced lipolysis, can involve a significant length oftherapy time. In contrast, the action of irreversible electroporationcan be much more rapid. Some known tissue ablation methods employingirreversible electroporation, however, involve destroying a significantmass of tissue, and one concern the temperature increase in the tissueresulting from this ablation process.

While pulsed DC voltages are known to drive irreversible electroporationunder the right circumstances, the examples of electroporationapplications in medicine and delivery methods described in the prior artdo not sufficiently discuss specificity and rapidity of action, ormethods to treat a local region of tissue with irreversibleelectroporation while not applying electroporation to adjoining regionsof tissue.

Thus, there is a need for selective energy delivery for electroporationand its modulation in various tissue types as well as pulses that permitrapid action and completion of therapy delivery. There is also a needfor more effective generation of voltage pulses and control methods, aswell as appropriate devices or tools addressing a variety of specificclinical applications. Such more selective and effective electroporationdelivery methods can broaden the areas of clinical application ofirreversible electroporation including therapeutic treatment to reducethe volume of adipose or fat tissue and the treatment of tumors ofvarious types.

SUMMARY

The embodiments described herein address the need for tools and methodsfor rapid and selective application of irreversible electroporationtherapy as well as pulse generation and control methods. The process ofirreversible electroporation can be induced even without the flow ofcurrent when a polarizing high voltage is applied to generate a suitablylarge electric field in a region of interest. The embodiments describedherein can result in well-controlled and specific delivery ofelectroporation in an efficacious manner.

In some embodiments, an apparatus includes a clamp, a first electrodehead and a second electrode head. The clamp includes a first arm and asecond arm, each configured to exert opposing forces to maintain atarget tissue disposed therebetween. The first electrode head is coupledto the first arm. The first electrode head includes a first electricallyinsulating contact surface, a first electrode and a first cooling unit.The first contact surface is configured to contact a first portion ofthe target tissue. The first cooling unit is configured to maintain thefirst portion of the target tissue at a first target temperature. Thesecond electrode head is coupled to the second arm, and includes asecond electrically insulating contact surface, a second electrode and asecond cooling unit. The second contact surface is configured to contacta second portion of the target tissue. The second cooling unit isconfigured to maintain the second portion of the target tissue at asecond target temperature. The first electrode and the second electrodeare collectively configured to deliver a voltage pulse to the targettissue.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a schematic illustration of an irreversible electroporationsystem that includes a DC voltage/signal generator, a controller capableof being configured to apply voltages to selected subsets of electrodes,and one or more medical devices connected to the controller.

FIG. 1B is a schematic illustration of an irreversible electroporationsystem that includes a DC voltage/signal generator and a controlleraccording to an embodiment.

FIG. 2 is a schematic illustration of a waveform generated by theirreversible electroporation system according to an embodiment, showinga balanced rectangular wave.

FIG. 3 is a schematic illustration of a waveform generated by theirreversible electroporation system according to an embodiment, showinga balanced biphasic rectangular wave.

FIG. 4 is a schematic illustration of a waveform generated by theirreversible electroporation system according to an embodiment, showinga progressive balanced biphasic rectangular wave.

FIG. 5 is a schematic illustration of a fat ablation electrode clampdevice according to an embodiment, where an electrode system isschematically shown clamped around target tissue.

FIG. 6 is a schematic illustration of a fat ablation electrode clampdevice according to an embodiment, where different parts of theelectrode system are shown schematically.

FIG. 7 is a schematic illustration of a fat ablation electrode clampdevice according to an embodiment, where multiple electrodes are shownon each clamp, the electrode heads incorporating means for solid statecooling, and including a means for adjusting the separation betweenelectrode clamps.

FIG. 8 is a schematic illustration of an electrode head design accordingto an embodiment incorporating means for solid state cooling.

FIG. 9 is a schematic illustration of an individual thermoelectriccooling unit.

FIG. 10 is a schematic illustration of a thermoelectric cooling moduleaccording to an embodiment incorporating a multiplicity ofthermoelectric cooling units.

FIG. 11 is a schematic illustration of electrode clamp device placementgeometry in relation to patient anatomy, according to an embodiment.

FIG. 12 is a schematic illustration of an electrode clamp deviceaccording to an embodiment showing electrode heads with large aspectratio.

FIG. 13 is a schematic illustration of electrode clamps according to anembodiment with large aspect ratio electrode heads showing overallplacement geometry in relation to patient anatomy.

FIG. 14 is a schematic illustration of an electrode clamp device forirreversible electroporation according to an embodiment, furtherincorporating means for sensing separation or distance in the form ofsuitable sensors mounted away from the electrode heads.

FIG. 15 is a schematic illustration of an electrode clamp device forirreversible electroporation according to an embodiment, furtherincorporating means for sensing separation or distance in the form ofsuitable sensors mounted on the electrode heads.

DETAILED DESCRIPTION

Medical systems, tools and methods are disclosed for the selective andrapid application of DC voltage to drive electroporation. In someembodiments, an apparatus includes a clamp, a first electrode head and asecond electrode head. The clamp includes a first arm and a second arm,each configured to exert opposing forces to maintain a target tissuedisposed therebetween. The first electrode head is coupled to the firstarm. The first electrode head includes a first electrically insulatingcontact surface, a first electrode and a first cooling unit. The firstcontact surface is configured to contact a first portion of the targettissue. The first cooling unit is configured to maintain the firstportion of the target tissue at a first target temperature. The secondelectrode head is coupled to the second arm, and includes a secondelectrically insulating contact surface, a second electrode and a secondcooling unit. The second contact surface is configured to contact asecond portion of the target tissue. The second cooling unit isconfigured to maintain the second portion of the target tissue at asecond target temperature. The first electrode and the second electrodeare collectively configured to deliver a voltage pulse to the targettissue.

In some embodiments, an apparatus includes a voltage pulse generatorconfigured to produce a pulsed voltage waveform, and an electrodecontroller. The electrode controller is configured to be operablycoupled to the voltage pulse generator and a medical clamp. The medicalclamp includes a plurality of electrodes. The electrode controller isimplemented in at least one of a memory or a processor, and includes afeedback module, a cooling module and a pulse delivery module. Thefeedback module is configured to determine a temperature of a targettissue to which the medical clamp is coupled. The cooling module isconfigured to produce a signal to a cooling unit of the medical clamp tomaintain a portion of the target tissue at a target temperature. Thepulse delivery module is configured to deliver an output signalassociated with the pulsed voltage waveform to the plurality ofelectrodes.

In some embodiments, a non-transitory processor readable medium storingcode representing instructions to be executed by a processor includescode to cause the processor to determine a temperature of a targettissue to which a medical clamp is coupled. The medical clamp includes aplurality of electrodes. The code further includes code to produce asignal based at least in part on the temperature of the target tissue.The signal is delivered to a cooling unit of the medical clamp tomaintain a portion of the target tissue at a target temperature. Thecode further includes code to deliver an output signal associated withthe pulsed voltage waveform to the plurality of electrodes when thetarget tissue is at the target temperature.

In some embodiments, a method includes receiving, at a feedback moduleof an electrode controller, a signal associated with a temperature of atarget tissue to which a medical clamp is coupled. The medical clampincludes a plurality of electrodes. A signal based at least in part onthe temperature of the target tissue is produced. The signal is thendelivered to a cooling unit of the medical clamp to maintain a portionof the target tissue at a target temperature. The method includesdelivering an output signal associated with the pulsed voltage waveformto the plurality of electrodes when the target tissue is at the targettemperature.

In some embodiments, an irreversible electroporation system includes aDC voltage/signal generator and a controller capable of being configuredto apply voltages to a selected multiplicity of electrodes. Further, thecontroller is capable of applying control inputs whereby selected pairsof anode-cathode subsets of electrodes can be sequentially updated basedon a pre-determined sequence. In some embodiments, the controller canfurther receive at least one temperature input, and based on atemperature input the controller can modify or update a controlparameter that can help to maintain a temperature value near a region ofinterest. The generator can output waveforms that can be selected togenerate a sequence of voltage pulses in either monophasic or biphasicforms and with either constant or progressively changing amplitudes.

Devices are disclosed for the selective electroporation ablation ofparticular tissue type (e.g., adipose tissue) while preservingsurrounding tissue of other types. In some embodiments, the system caninclude a means for sensing electrode separation, and the electrodevoltage applied can be determined based on a sensed separation ordistance measure. This determination can be fully or partiallyautomatic, or manual.

In some embodiments, a system uses temperature to selectively ablatetissue as the threshold of irreversible electroporation istemperature-dependent, utilizing means such as the suitable use ofcooling fluid or solid state cooling methods to locally raise theirreversible electroporation threshold electric field value and therebyselecting the predominant tissue type or region it is desired to ablate.In contrast to the process of adipose tissue reduction by freezing, alsoknown as cryogenically induced lipolysis, which uses lower temperaturesto directly freeze adipose tissue, the lowered temperatures according toan embodiment assist in the selective action of irreversibleelectroporation, a much more rapid process than freezing.

In some embodiments, an irreversible electroporation system includes aDC voltage/signal generator and a controller that is configured to applyvoltages to a selected multiplicity or a subset of electrodes. In someembodiments, a temperature measurement device such as a thermistormeasures temperature at or near a portion of an electrode device. Thecontroller is capable of applying control inputs whereby the temperatureat or near a portion of the device is maintained within a narrow rangeof desired values. Preferably, the temperature at or near an electrodeor electrode head surface contacting a patient anatomy is maintained ator near a value that is lower than body temperature. In someembodiments, the application of DC voltage pulses is made only when thetemperature is within a narrow range of values around a desired value.In some embodiments, at least one control input for temperature controltakes the form of rate of flow of a cooling fluid, while in anotherembodiment, the control input is a voltage that drives a thermoelectricheat pump. Further, in some embodiments, the electrode clamp devicedisclosed here incorporates a sensor to measure a separation distance,based on which the electroporation voltage value is selected.

A DC voltage for electroporation can be applied to subsets of electrodesidentified as anode and cathode respectively on opposite sides of ananatomical region it is desired to ablate. The DC voltage is applied inbrief pulses sufficient to cause irreversible electroporation and canpreferably be in the range of 0.5 kV to 60 kV and more preferably in therange 1 kV to 10 kV, so that an appropriate threshold electric fieldvalue of at least around 800 Volts/cm is effectively achieved in thetissue (for example, adipose tissue) to be ablated. In some embodiments,the DC voltage generator setting for irreversible electroporation isautomatically identified by the electroporation system based on a senseddistance measuring the spatial separation between electrodes of opposingpolarities. In an alternate embodiment, the DC voltage value is selecteddirectly by a user from a suitable dial, slider, touch screen, or anyother user interface. In some embodiments, while transient currents maybe induced in the tissue upon voltage application or removal, there areno other (steady state) currents as the electrodes are insulated fromthe subject anatomy. A region or volume of tissue where the electricfield is sufficiently large for irreversible electroporation to occur isablated during the DC voltage pulse application. At the same time, theapplication of surface cooling raises the electroporation threshold oftissue near the surface and prevents the occurrence of irreversibleelectroporation in this surface layer.

As used in this specification, the singular forms “a,” “an” and “the”include plural referents unless the context clearly dictates otherwise.Thus, for example, the term “a member” is intended to mean a singlemember or a combination of members, “a material” is intended to mean oneor more materials, “a processor” is intended to mean a single processoror multiple processors; and “memory” is intended to mean one or morememories, or a combination thereof.

As used herein, the terms “about” and “approximately” generally meanplus or minus 10% of the value stated. For example, about 0.5 wouldinclude 0.45 and 0.55, about 10 would include 9 to 11, about 1000 wouldinclude 900 to 1100.

A schematic diagram of the electroporation system according to anembodiment is shown in FIG. 1A. The system includes a DC voltage/signalgenerator 23 is driven by a controller unit 21 that interfaces with acomputer device 24 by means of a two-way communication link 29. Thecontroller can perform channel selection and routing functions forapplying DC voltages to appropriate electrodes that have been selectedby a user or by the computer 24, and apply the voltages via amultiplicity of leads (shown collectively as 26) to an electrode device22. The electrode device 22, and any of the electrode devices describedherein can be similar to the ablation catheters described in PCTPublication No. WO2014/025394, entitled “Catheters, Catheter Systems,and Methods for Puncturing Through a Tissue Structure,” filed on Mar.14, 2013 (“the '394 PCT Application), which is incorporated herein byreference in its entirety.

Some of the leads 26 from the controller 21 can also carry controlsignals to adjust temperature at or near the electrode device. In analternate embodiment, the control signals from the controller 21 can berouted to a different unit (not shown) such as a cooling pump forexample, to control cooling fluid flow rate). The electrode device 22can also send information and/or signals to the controller 21, such astemperature data from sensors mounted on or near the electrode device.Such feedback signals are indicated by the data stream 25, which can besent via separate leads. While the DC voltage generator 23 sends a DCvoltage to the controller 21 through leads 27, the voltage generator isdriven by control and timing inputs 28 from the controller unit 21.

In some embodiments, the electrode controller can include one or moremodules and can automatically control the temperature of a targettissue, adjust a characteristic of the voltage waveform based on thespacing between adjacent electrodes, or the like. For example, FIG. 1Bshows an electroporation system according to an embodiment that includesan electrode controller 900 and a signal generator 925. The electrodecontroller 900 is coupled to a computer 920 or other input/outputdevice, and is configured to be operably coupled to a medical device930. The medical device 930 can be one or more of the medical clamps ofthe types shown and described herein. Further the medical device 930 canbe coupled to, disposed about and/or in contact with a target tissue T.In this manner, as described herein, the electroporation system,including the electrode controller 900 and the signal generator 925, candeliver voltage pulses to the target tissue for therapeutic purposes.

The controller 900 can include a memory 911, a processor 910, and aninput/output module (or interface) 901. The controller 900 can alsoinclude a temperature control module 902, a feedback module 905, and apulse delivery module 908. The electrode controller 900 is coupled to acomputer 920 or other input/output device via the input/output module(or interface) 901.

The processor 910 can be any processor configured to, for example, writedata into and read data from the memory 911, and execute theinstructions and/or methods stored within the memory 911. Furthermore,the processor 910 can be configured to control operation of the othermodules within the controller (e.g., the temperature control module 902,the feedback module 905, and the pulse delivery module 908).Specifically, the processor 910 can receive a signal including userinput, temperature data, distance measurements or the like and determinea set of electrodes to which voltage pulses should be applied, thedesired timing and sequence of the voltage pulses and the like. In otherembodiments, the processor 910 can be, for example, anapplication-specific integrated circuit (ASIC) or a combination ofASICs, which are designed to perform one or more specific functions. Inyet other embodiments, the microprocessor can be an analog or digitalcircuit, or a combination of multiple circuits.

The memory device 911 can be any suitable device such as, for example, aread only memory (ROM) component, a random access memory (RAM)component, electronically programmable read only memory (EPROM),erasable electronically programmable read only memory (EEPROM),registers, cache memory, and/or flash memory. Any of the modules (thetemperature control module 902, the feedback module 905, and the pulsedelivery module 908) can be implemented by the processor 910 and/orstored within the memory 911.

As shown, the electrode controller 900 operably coupled to the signalgenerator 925. The signal generator includes circuitry, componentsand/or code to produce a series of DC voltage pulses for delivery toelectrodes included within the medical device 930. For example, in someembodiments, the signal generator 925 can be configured to produce abiphasic waveform having a pre-polarizing pulse followed by a polarizingpulse. The signal generator 925 can be any suitable signal generator ofthe types shown and described herein.

The pulse delivery module 908 of the electrode controller 900 includescircuitry, components and/or code to deliver an output signal associatedwith the pulsed voltage waveform produced by the signal generator 925.This signal (shown as signal 909) can be any signal of the types shownand described herein, and can be of a type and/or have characteristicsto be therapeutically effective. In some embodiments, the pulse deliverymodule 908 receives input from other portions of the system, and cantherefore send the signal 909 to the appropriate subset of electrodes,as described herein.

The electrode controller 900 includes the temperature control module902. The temperature control module 902 includes circuitry, componentsand/or code to produce a control signal (identified as signal 903) thatcan be delivered to the cooling unit (not shown) of the medical device930 to facilitate cooling of a portion of the tissue T.

In some embodiments, the ablation controller and signal generator can bemounted on a rolling trolley, and the user can control the device usinga touchscreen interface that could possibly be in the sterile field. Thetouchscreen can be for example an LCD touchscreen in a plastic housingmountable to a standard medical rail or post and can be used to selectthe electrodes for ablation and to ready the device to fire. Theinterface can for example be covered with a clear sterile plastic drape.The operator can select the electrodes involved in an automatedsequence, if any. The touch screen graphically shows the catheters thatare attached to the controller. In one embodiment the operator canselect electrodes from the touchscreen with appropriate graphicalbuttons. The ablation sequence can be initiated by holding down ahand-held trigger button that is possibly in a sterile field. Thehand-held trigger button can be illuminated red to indicate that thedevice is “armed” and ready to ablate. The trigger button can becompatible for use in a sterile field and when attached to thecontroller can be illuminated a different color, for example white. Insome embodiments, the “armed” state of the trigger can depend on whetherthe electrode temperature is within a desired range of values; if not,an appropriate control signal is applied to bring the temperature backto the desired range. When the device is firing, the trigger buttonflashes in sequence with the pulse delivery in a specific color such asred. The waveform of each delivered pulse is displayed on thetouchscreen interface.

The waveforms for the various electrodes can be displayed and recordedon the case monitor and simultaneously outputted to a standard dataacquisition system. With the high voltages involved with the device, theoutputs to the data acquisition system are protected from voltage and/orcurrent surges. The waveform amplitude, period, duty cycle, and delaycan all be modified, for example via a suitable Ethernet connection.

In some embodiments, a system (generator and controller) according to anembodiment can deliver rectangular-wave pulses with a peak maximumvoltage of up to about 10 kV into a load with an impedance in the rangeof 30 Ohm to 3000 Ohm for a maximum duration of 200 μs. In someembodiments the maximum duration can be 100 μs. The load can be part ofthe electrode circuitry, so that power is harmlessly dissipated in theload. Pulses can be delivered in a multiplexed and synchronized mannerto a multi-electrode device with a duty cycle of up to 50% (for shortbursts). The pulses can generally be delivered in bursts, such as forexample a sequence of between 2 and 10 pulses interrupted by pauses ofbetween 1 ms and 1000 ms. In one embodiment, the multiplexer controlleris capable of running an automated sequence to deliver theimpulses/impulse trains (from the DC voltage signal/impulse generator)to the tissue target as a sequence of pulses over electrodes. Thecontroller system is capable of switching between subsets of electrodeslocated on the electrode device.

In some embodiments, the controller can have several pulse sequenceconfigurations that provide the operator with at least some variety ofprogramming options. In one configuration, the controller can switchelectrode configurations of a bipolar set of electrodes (cathode andanode) sequentially along the length of an electrode clamp device. Theuser can control the application of DC voltage with a single handheldswitch. A sterile catheter or catheters can be connected to the voltageoutput of the generator via a connector cable. In one embodiment, theuser activates the device with a touch screen. The generator can remainin a standby mode until the user is ready to apply pulses at which pointthe user/assistant can put the generator into a ready mode via thetouchscreen interface. Subsequently the user can select the sequence andthe active electrodes.

In some embodiments, any of the systems described herein can select anappropriate voltage value based on a distance measurement betweenelectrodes of opposing polarities. In this manner, the system can ensurethat an electric field sufficient to cause irreversible electroporationis applied up to the desired depth.

The controller and generator can output waveforms that can be selectedto generate a sequence of voltage pulses in either monophasic orbiphasic forms and with either constant or progressively changingamplitudes. FIG. 2 shows a square or rectangular wave pulse train wherethe pulses 101 have a uniform height or maximum voltage. FIG. 3 shows anexample of a balanced biphasic rectangular pulse train, where eachpositive voltage pulse such as 103 is immediately followed by a negativevoltage pulse such as 104 of equal amplitude and opposite sign. While inthis example the biphasic pulses are balanced with equal amplitudes ofthe positive and negative voltages, in other embodiments an unbalancedbiphasic waveform could also be used as may be convenient for a givenapplication.

A train of multiple DC voltage pulses can be applied to ensure thatsufficient tissue ablation has occurred. Further, the user can repeatthe delivery of irreversible electroporation over several successivepulse trains for further confidence.

Yet another example of a waveform or pulse shape that can be generatedby any of the systems described herein is illustrated in FIG. 4 , whichshows a progressive balanced rectangular pulse train. In this pulsetrain, each distinct biphasic pulse has equal-amplitude positive andnegative voltages, but each pulse such as 107 is larger in amplitudethan its immediate predecessor 106. Other variations such as aprogressive unbalanced rectangular pulse train, or indeed a wide varietyof other variations of pulse amplitude with respect to time can beconceived and implemented by those skilled in the art based on theteachings herein.

The time duration of each irreversible electroporation rectangularvoltage pulse could lie in the range from 1 nanosecond to 10milliseconds, with the range 10 microseconds to 1 millisecond being morepreferable and the range 50 microseconds to 300 microseconds being stillmore preferable. The time interval between successive pulses of a pulsetrain could be in the range of 10 microseconds to 1 millisecond, withthe range 50 microseconds to 300 microseconds being more preferable. Thenumber of pulses applied in a single pulse train (with delays betweenindividual pulses lying in the ranges just mentioned) can range from 1to 100, with the range 1 to 10 being more preferable. As described inthe foregoing, a pulse train can be driven by a user-controlled switchor button, in one embodiment preferably mounted on a hand-heldjoystick-like device. In one mode of operation a pulse train can begenerated for every push of such a control button, while in an alternatemode of operation pulse trains can be generated repeatedly during therefractory periods of a set of successive cardiac cycles, for as long asthe user-controlled switch or button is engaged by the user.

All of these parameters can be determined by the design of the signalgenerator, and in various embodiments could also be determined by usercontrol as may be convenient for a given clinical application. Thespecific examples and descriptions herein are exemplary in nature andvariations can be developed by those skilled in the art based on thematerial taught herein without departing from the scope according to anembodiment, which is limited only by the attached claims.

In some embodiments, an irreversible electroporation ablation system ofthe type shown and described herein can be used for adipose tissue (orfat) ablation for the reduction or elimination of adipose tissue. Asmentioned earlier, various tissue or cell types have differentirreversible electroporation thresholds. Fat cells typically have anirreversible electroporation threshold in the range of 800 Volts/cm.FIG. 5 shows an electrode clamp device that externally clamps onto afold of skin on a patient anatomy, with electrode clamp arms 211connected to a clamp head 210 including springs, screw or othertightening mechanisms for firmly positioning the electrodes in a clampedposition. The electrode clamp arms end in electrode heads 212 thatincorporate cooling coils 219 that carry a cooling fluid at atemperature sufficient to cool and maintain the skin temperature atabout approximately 50 degrees Fahrenheit. A cooling system and drivepump (not shown) with a controllable fluid flow rate supply coolant tomaintain the electrode temperature at or near a suitably low value (suchas, for example, 50 degrees Fahrenheit). The electrodes are shownclamping on to tissue in the form of a layer of skin 215 with fattytissue 214 beneath the skin. Each electrode itself is located internallywithin its electrode head and the latter is made of insulating material,so that no conductor touches the patient surface. FIG. 5 shows anexample of electric field lines 217 generated in the tissue when a DCvoltage is applied across the electrodes.

As shown in FIG. 5 , since the patient-contacting surfaces areinsulators, there is no steady state charge transfer or direct currentwithin the tissue. However, the polarizing electric field applied inpulses can generate irreversible electroporation in the tissue andgenerate induced or transient currents in the tissue. The irreversibleelectroporation threshold of tissue increases as temperature decreases.Thus, by cooling the electrodes and the layer of skin, the skin tissue'selectroporation threshold can be increased beyond the approximately 800V/cm threshold value of fat tissue. When a DC electric field of suitablestrength is applied, fat (indicated by 214 in FIG. 5 ) can therefore beselectively ablated by electroporation while maintaining the integrityof skin tissue (indicated by 215 in FIG. 5 ) as long as the appliedelectric field is in the range between the irreversible electroporationthresholds of adipose tissue and the cooled skin tissue.

FIG. 6 is a schematic illustration of an electrode head of the electrodeclamp device showing the electrodes or electroporation probes 233situated within an outer casing 231. Coolant coils 235 within eachelectrode head keep the electrode head surface cold and maintain theskin temperature at approximately 50 degrees Fahrenheit. Thepatient-contacting surface 239 of each electrode head is an insulator,so that there is no direct current transfer between the electrodes. Theparallel electrodes act like capacitor plates for very brief periods asDC voltage pulses are applied for irreversible electroporation. Theelectric field 237 generated between the electrodes in the tissue regionserves to polarize the tissue and generate irreversible electroporationin the fat or adipose tissue. The voltage pulses induce brief transientcurrents in the tissue when the field changes but no steady state directcurrent. Thus with this device, inductive irreversible electroporationcan be generated. The applied DC voltage can be made to depend on thedistance between the electrodes. In one embodiment, the electrode clampcan have a discrete number of possible relative positions of theelectrodes with pre-determined separation distances. Based on theseparation, a sufficient voltage that generates at least anapproximately 800 Volts/cm electric field between the electrodes can becomputed by the electroporation system and applied for the selectiveirreversible electroporation of adipose tissue.

FIG. 7 shows an electrode clamp device that externally clamps onto afold of skin on a patient anatomy, with electrode clamp arms 301 and 302connected to a clamp head 314 including a screw mechanism 319 for firmlypositioning the electrodes in a clamped position around a portion ofpatient anatomy, with a fixed distance between electrode arms. The topelectrode arm 301 has disposed along it electrode heads 305, 306 and 307respectively aligned with electrode heads 315, 316 and 317 on the bottomelectrode arm 302. In FIG. 7 , the lower electrode arm 302 is fixed to amount (not shown) and the screw mechanism allows for the vertical motionof electrode arm 301 relative to electrode arm 302, thereby permittingadjustment of the separation distance between the arms over a range ofvalues. In some embodiments, the electrode heads can incorporatethermoelectric cooling modules for keeping the patient-contacting faceof each electrode at a cooled temperature significantly below bodytemperature (for example, the patient contacting face of the electrodecan be maintained in a narrow range around 50 degrees Fahrenheit). Thiscan be done with a thermoelectric or solid state cooling module byapplying an appropriate voltage or current to the cooling module. Solidstate cooling has the advantage of having no moving parts withcorresponding convenience of design and implementation.

As an example, referring to FIG. 7 bipolar leads 310, 311 and 312 attachto electrode heads 305, 306 and 307 respectively in order to control thetemperature on the patient contacting electrode face of each electrode.When an appropriate voltage is applied across a Peltier cooling module,it functions as a heat pump, transferring heat from one face of themodule to the other. Furthermore, each electrode head, or at least eachelectrode arm, can incorporate a temperature sensing unit such as athermistor 297 shown attached to leads 298 on electrode arm 302. Thedata from the temperature sensing unit is read by the controller (notshown in FIG. 7 ) or to a computer where the temperature data isutilized to generate an appropriate control signal for the purpose ofmaintaining electrode face temperature by using any of a range ofcontrol schemes or methods, for example PID(Proportional-Integral-Derivative) control.

FIG. 8 is a schematic illustration of an electrode head incorporatingmeans for solid state or thermoelectric cooling. A metal electrode 332for high voltage DC application abuts a ceramic cover 333 on one side(with the outside face of the ceramic cover being a patient contactingface) and a thermoelectric or Peltier cooling module 331 on the other.The top face of the cooling module 331 is adjacent to a ceramic cover330, so that the entire electrode head has ceramic faces on both top andbottom faces.

FIG. 9 schematically illustrates a thermoelectric or Peltier coolingunit, a multiplicity of which can be arranged to form a Peltier coolingmodule. The thermoelectric unit comprises a p-type semiconductor 401(such as for example Lead Telluride) electrically in series with ann-type semiconductor 402 (such as for example Bismuth Telluride) andconnected by a metallic connection 404. At the same time, thesemiconductors 401 and 402 are thermally connected in parallel. Thedisjoint ends of the p-type semiconductor and the n-type semiconductorare connected to metallic terminal electrodes 406 and 407 respectivelywith negative and positive electric polarities or voltages respectively,and the electrodes 406 and 407 abut a ceramic cover 408. When a voltageis applied to the terminal electrodes (so that terminal 406 is at anegative electric potential relative to terminal 407), a current flowsfrom the n-type semiconductor 402 through the series connection 404 andthrough the p-type semiconductor 401. The respective charge carriers ineach semiconductor move from the top to the bottom, and correspondinglythere is a heat flux that transports heat from the top face 404 of thePeltier cooling unit to the bottom face 408. Correspondingly 404 isturned into the “cold” or lower temperature face and 408 into the “hot”or higher temperature face of the Peltier cooling unit.

FIG. 10 schematically depicts a chain of Peltier cooling units connectedto form a thermoelectric cooling module. In this example, the module 453comprises Peltier cooling units 458, 459, 460, 461, 462, 463, 464 and465 connected in a chain so as to spread approximately uniformly over anarea and such that all the units have for example a “hot side” on thebottom and a “cold” side on the top. An appropriate voltage can beapplied across the end terminal leads 455 and 456 in order to drive aheat flux between the top and bottom sides and maintain a cold surface.

Thermoelectric heat pump modules are commercially available, for examplefrom sources such as TE Technology, Inc. of Traverse City, Mich., USAand appropriate configurations convenient for the electrode clampdevices according to an embodiment can be arrived at by those skilled inthe art.

FIG. 11 schematically illustrates one geometry of use of the electrodeclamp device, wherein a portion 347 of skin and adipose tissue 342disposed around a patient anatomy 341 is clamped between electrode arms344 and 345 for electroporation ablation. FIG. 12 is an illustration ofan electrode clamp device with electrode arms 301 and 302 wherein theirrespective electrode heads 326 and 327 are longitudinally disposed andhave large aspect ratios, as shown schematically therein. As shown inthe geometry depicted schematically in FIG. 13 , such an arrangementcould be used to clamp, in a lengthwise disposition, a portion of skinand adipose tissue 342 disposed around a patient anatomy 341 betweenelectrode arms 344 and 345 for electroporation ablation.

In some embodiments, the time for which a cold temperature is maintainedat the patient contacting surface of the electrode head is monitored andvaried, so that the cooling control is applied in time in a pulse-likeformat. This is done in order to maintain a surface layer of tissue at asuitably low or cold temperature, while ensuring that deeper regions oftissue undergo no more than marginal cooling. The thermal diffusivity Dof skin tissue is known to be in the range of 0.11 mm²/s. From standardheat diffusion theory, in a time T the depth x to which a temperaturechange applied at the surface is propagated is given (in two dimensions)by x˜√{square root over (2DT)}; in 20 seconds of cooling, we have x˜2mm, about the thickness of skin tissue. In one mode of operation of thesystem according to an embodiment, the cooling of the electrodes isperformed in discrete time intervals in the range of 10 seconds to 40seconds, followed by a pulse train application, the entire duration ofthe pulse train being in the range of less than about 8 seconds. Thus,the application of cooling could also be performed in pulses. The nextablation in the same tissue region is performed, if necessary, afteranother cooling pulse is applied over a discrete time interval, and soon. In some embodiments, a heating pulse could follow a cooling pulse inorder to ensure that the temperature in the interior of the tissue doesnot fall below a threshold value. Such a heating pulse can be appliedwhen a thermoelectric or Peltier heat pump is used simply by reversingthe polarity of the (voltage) control signal to the heat pump, and theheating pulse could have a duration in the range between 2 and 30seconds.

FIG. 14 illustrates schematically one embodiment, where the electrodeclamp device with electrode arms 301 and 302 with respective electrodeheads 305 and 35 further has a sensor for measuring separation distance,in the form of an electromagnetic transmitter 352 on electrode arm 302and an electromagnetic receiver coil 350 on electrode arm 301. Leads 354and 355 respectively connect to receiver 350 and transmitter 352. Basedon the signal intensity received by the receiver 350, the distance ofseparation d indicated by 355 in the FIG. can be measured. For example,if the axes and centers of the transmitter and receiver sensors arealigned, and a current I flows through the transmitter (of radius a),the magnetic field B at the center of the receiver is given by

$\begin{matrix}{B = \frac{\mu_{0}{Ia}^{2}}{2\left( {d^{2} + a^{2}} \right)^{3\text{/}2}}} & (1)\end{matrix}$where μ₀ is the magnetic permeability of free space. If the current inthe transmitter is sinusoidal with circular frequency ω, the timevarying magnetic field induces a voltage in the receiver given to a goodapproximation by

$\begin{matrix}{V = {\omega\;\frac{\mu_{0}{Ia}^{2}A}{2\left( {d^{2} + a^{2}} \right)^{3\text{/}2}}}} & (2)\end{matrix}$where A is the area of the receiver. Thus by measuring the inducedvoltage V, the separation distance d can be determined.

While in FIG. 14 the transmitter and receiver sensors for distancedetermination were located at a separation away from the electrode headsto mitigate electromagnetic interference with the metallic electrodes,in an alternate embodiment, the transmitter and receiver sensors couldbe integrated within an electrode head, as shown schematically in FIG.15 . In FIG. 15 , the transmitter 352 is incorporated in electrode head315 of lower electrode arm 302, while receiver sensor 350 isincorporated in electrode head 305 of upper electrode arm 301. Alsoshown are other electrode heads 306, 307, 316 and 317. With thisarrangement, the induced voltage at the receiver is calibrated over arange of separations of the electrode arms, in effect generating alookup table. The electromagnetic interference of the electrode heads isimplicitly accounted for by this calibration process; subsequently,given a measured induced voltage at the receiver, the separationdistance can be determined from the calibration data.

While the foregoing described one method of separation distancedetermination based on an electromagnetic scheme purely for illustrativeand exemplary purposes, it should be apparent that a variety of othermethods are available for this purpose such as for example schemes basedon the use of ultrasound transmitters and receivers or infraredtransmitters and receivers. Based on the teachings herein, those skilledin the art could arrive at an implementation that may be convenient fora specific application.

With a separation distance between electrode heads thus determined, theapplied voltage to the electrode heads is then correspondinglydetermined based on a desired irreversible electroporation thresholdvalue. For example, if the distance between electrode heads is measuredto be 4 cm, and the desired irreversible electroporation threshold valueis an electric field of 800 Volts/cm, it is clear that a voltage of atleast 3.2 kV (desired electric field times distance) needs to be appliedbetween the electrodes in order to meet or exceed the threshold valuefor irreversible electroporation.

Some embodiments described herein relate to a computer storage productwith a non-transitory computer-readable medium (also can be referred toas a non-transitory processor-readable medium) having instructions orcomputer code thereon for performing various computer-implementedoperations. The computer-readable medium (or processor-readable medium)is non-transitory in the sense that it does not include transitorypropagating signals per se (e.g., a propagating electromagnetic wavecarrying information on a transmission medium such as space or a cable).The media and computer code (also can be referred to as code) may bethose designed and constructed for the specific purpose or purposes.Examples of non-transitory computer-readable media include, but are notlimited to: magnetic storage media such as hard disks, floppy disks, andmagnetic tape; optical storage media such as Compact Disc/Digital VideoDiscs (CD/DVDs), Compact Disc-Read Only Memories (CD-ROMs), andholographic devices; magneto-optical storage media such as opticaldisks; carrier wave signal processing modules; and hardware devices thatare specially configured to store and execute program code, such asApplication-Specific Integrated Circuits (ASICs), Programmable LogicDevices (PLDs), Read-Only Memory (ROM) and Random-Access Memory (RAM)devices.

Examples of computer code include, but are not limited to, micro-code ormicro-instructions, machine instructions, such as produced by acompiler, code used to produce a web service, and files containinghigher-level instructions that are executed by a computer using aninterpreter. For example, embodiments may be implemented usingimperative programming languages (e.g., C, Fortran, etc.), functionalprogramming languages (Haskell, Erlang, etc.), logical programminglanguages (e.g., Prolog), object-oriented programming languages (e.g.,Java, C++, etc.) or other suitable programming languages and/ordevelopment tools. Additional examples of computer code include, but arenot limited to, control signals, encrypted code, and compressed code.

While various specific examples and embodiments of systems and tools forselective tissue ablation with irreversible electroporation weredescribed in the foregoing for illustrative and exemplary purposes, itshould be clear that a wide variety of variations and alternateembodiments could be conceived or constructed by those skilled in theart based on the teachings according to an embodiment. While specificmethods of control and DC voltage application from a generator capableof selective excitation of sets of electrodes were disclosed togetherwith temperature control, persons skilled in the art would recognizethat any of a wide variety of other control or user input methods can beimplemented without departing from the scope according to an embodiment.Likewise, while the foregoing described a range of specific tools ordevices for more effective and selective DC voltage application forirreversible electroporation through an externally applied electrodeclamp device, other device constructions or variations could beimplemented by one skilled in the art by employing the principles andteachings disclosed herein without departing from the scope according toan embodiment, in the treatment of excessive adipose tissue, tumorablation, or a variety of other medical applications.

Furthermore, while the present disclosure describes specific embodimentsand tools involving the use of temperature to selectively ablate tissueby taking advantage of the temperature-dependence of the threshold ofirreversible electroporation and the application of specific coolingmethodologies for exemplary purposes, it should be clear to one skilledin the art that a variety of methods and devices for fluid pumping andcontrol, for tissue or electrode cooling, or even for tissue heatingthrough the delivery of focused kinetic energy or electromagneticradiation could be implemented utilizing the methods and principlestaught herein without departing from the scope according to anembodiment.

Accordingly, while many variations of methods and tools disclosed herecan be constructed, the scope according to an embodiment is limited onlyby the appended claims.

The invention claimed is:
 1. An apparatus, comprising: a voltage pulsegenerator configured to produce a pulsed voltage waveform, the pulsedvoltage waveform including a plurality of pulses; a medical clampincluding a first arm and a second arm, the first arm and the second armdefining a volume to receive a target tissue, the first arm configuredto be spaced apart from the second arm by a distance, the medical claimincluding a plurality of electrodes; and an electrode controllerconfigured to be operably coupled to the voltage pulse generator, theelectrode controller implemented in at least one of a memory or aprocessor, the electrode controller including: a feedback moduleconfigured to determine (i) the distance based on a measured valueassociated with the distance and (ii) a temperature of a target tissueto which the medical clamp is coupled; a cooling module configured toproduce and deliver a signal to a cooling unit of the medical clamp tomaintain a portion of the target tissue at a target temperature; and apulse delivery module configured to deliver an output signal associatedwith the pulsed voltage waveform, wherein a characteristic of the outputsignal is based on the determined distance, to a subset of electrodesfrom the plurality of electrodes to cause the subset of electrodes tocollectively generate a pulsed electric field that ablates the targettissue.
 2. The apparatus of claim 1, wherein the target temperature isbelow a body temperature.
 3. The apparatus of claim 1, wherein thetarget temperature is below about 55 degrees Fahrenheit.
 4. Theapparatus of claim 1, wherein the electrode controller is configured tointerface with an external device to program at least one of anamplitude of the output signal, a period of the output signal, or aduration of the output signal.
 5. The apparatus of claim 1, wherein thecooling module includes any one of a cooling coil, a thermo-electriccooler, or a heat pump.
 6. The apparatus of claim 1, wherein the coolingmodule is configured to produce the signal based at least in part on thetemperature of the target tissue.
 7. The apparatus of claim 1, whereinthe characteristic of the output signal is at least one of: an amplitudeof the output signal, a period of the output signal, or a duration ofthe output signal.
 8. The apparatus of claim 1, wherein the pulsewaveform has an amplitude between about 0.5 kilovolts (kV) and about 60kV.
 9. The apparatus claim 1, wherein the measured value is a voltageinduced in a receiver disposed on the first arm or the second arm by amagnetic field generated by a transmitter disposed on the other of thefirst arm or the second arm.
 10. The apparatus of claim 9, wherein thefeedback module is configured to determine the distance based on theinduced voltage, a current associated with the magnetic field, and oneor more parameters associated with the transmitter and the receiver. 11.The apparatus of claim 1, wherein the signal is a time-varying signalsuch that the time-varying signal, when delivered by the cooling moduleto the cooling unit, causes the cooing unit to apply cooling to theportion of the target tissue in pulses to maintain the portion of thetarget tissue at the target temperature.
 12. A non-transitory processorreadable medium storing code representing instructions to be executed bya processor, the code comprising code to cause the processor to:determine a temperature of a target tissue to which a medical clamp,having a first arm and a second arm separated by a distance, is coupled,the medical clamp including a plurality of electrodes; receive ameasured value associated with the distance; produce a control signalbased at least in part on the temperature of the target tissue; deliverthe control signal to a cooling unit of the medical clamp to maintain aportion of the target tissue at a target temperature; and deliver, tothe plurality of electrodes when the target tissue is at the targettemperature, an output signal associated with a pulsed voltage waveformincluding a plurality of pulses and generated by a signal generatoroperatively coupled to the processor, to cause the output signal togenerate a pulsed electric field to ablate the target tissue; whereinthe output signal is adjusted based on the measured value.
 13. A method,comprising: receiving a temperature signal associated with a temperatureof a target tissue to which a medical clamp is coupled, the medicalclamp including a plurality of electrodes, a first arm and a second arm,the first arm and the second arm defining a volume to receive the targettissue, the first arm configured to be spaced apart from the second armby a distance; producing a control signal based at least in part on thetemperature of the target tissue; delivering the control signal to acooling unit to maintain a portion of the target tissue at a targettemperature; receiving a measured value associated with the distance;generating a pulsed voltage waveform including a plurality of pulses,and delivering an output signal associated with the pulsed voltagewaveform, wherein a characteristic of the output signal is based on thedistance, to the plurality of electrodes when the target tissue is atthe target temperature to cause the output signal to generate a pulsedelectric field to ablate the target tissue.
 14. The method of claim 13,wherein the target temperature of the target tissue is below a bodytemperature.
 15. The method of claim 13, wherein the target temperatureof the target tissue is below about 55 degrees Fahrenheit.
 16. Themethod of claim 13, wherein the pulsed voltage waveform is greater thanapproximately one kilovolt (kV).
 17. The method of claim 13, wherein thedelivering the control signal to the cooling unit includes deliveringthe control signal to a pump such that the pump controls a flow rate ofdelivering a coolant fluid to the medical clamp based on the controlsignal.
 18. The method of claim 13, wherein the delivering the controlsignal to the cooling unit includes delivering, based on the controlsignal, a voltage or a current to a thermoelectric cooler.